This application is a 371 of PCT/JP97/03485, filed Sep. 30, 1997.
The present invention relates to a medicament for prophylactic and/or preventive and/or therapeutic treatment of diseases caused by mitochondrial functional abnormality or diseases with mitochondrial functional abnormality.
It is known that intracellular calcium ions (Ca+2) may become a cytotoxic factor when increased beyond a certain concentration, although they act as an important information transmitter under physiological conditions. In particular, in the nervous system under ischemic conditions, calcium ions flow into cells through the glutamic acid receptor (NMDA type) due to excessive glutamic acid and induce nerve necrosis (Choi, D. W., Trends in Neurosciences, 11, 465-469, 1988). Under healthy conditions, excessive calcium ions are taken into the endoplasmic reticulum and mitochondria when calcium ions flow into cells beyond a certain concentration, and as a result, calcium ion concentrations are homeostatically maintained.
However, when high levels of calcium ions are accumulated in mitochondria for a prolonged period of time and chronic hypoxic conditions are maintained in mitochondria, the mitochondrial energy-generating function (ability to synthesize ATP) becomes degraded, which results in stoppage of various ion pumps present in cellular membranes (Nicotera et al., Chem. Res. Toxico., 3, 484-494, 1990; and Zaiden et al., J. Neurochem., 63, 1812-1819, 1994). In addition, when the state of calcium ion influx is maintained, plasma membranes are depolarized. This may cause disinhibition of NMDA-type glutamate receptor/ion channel complex that is kept in a suppressed condition by magnesium ions, which leads to further acceleration of calcium ion influx as a vicious circle.
If the mitochondrial energy-generating function (ATP synthesis) can be maintained even at the condition of influx and accumulation of a high level of calcium ions in mitochondria, the function of the calcium ion pumps, that are present in plasma membranes, can be kept normal and concentrations of the influxed and accumulated calcium ions in the cells can be lowered. As a result, physiological conditions of the cells may be restored. However, it has been considered that the activation of the mitochondria is substantially impossible under the calcium influx by the reasons set out below.
Energy generation in mitochondria is performed by the process of aerobic glycolysis (TCA cycle). Protons (H+) are produced in the process (electron transfer system), and the generated energy is used to transfer the protons from the inner matrix of mitochondria to the outside.
Extremely high electrochemical potentials are generated across the mitochondrial inner membrane from the outside {1) mitochondrial membrane potentials (xcexa8m) approximately xe2x88x92150 mV and 2) chemical potentials derived from the difference in proton (H+) concentration across the mitochondrial inner membrane} (Loew et al., Proc. Natl. Acad. Sci., USA, 91, 12579-12583, 1994). The high potential energies based on the active transport of protons (H+) is then used to drive ATP synthesis (Kagawa, Y., Saibo Kogaku (Cell Technology), 11, 3-11, 1992).
However, under physiological conditions, when positively charged calcium ions flow into the mitochondrial matrix, these calcium ions are pumped out by consuming the energy generated by ATPase located in the mitochondrial matrix, so that the mitochondrial membrane potential can be maintained. However, under pathological conditions where ATP activity is degraded, ATPase activity is decreased and the pumping out of calcium ions may become insufficient, so that the potential of the mitochondrial matrix shifts to the positive, thereby reducing xcexa8m (decrease of electrical potential).
Under these pathological conditions (a state of depolarized mitochondrial membrane potential), even though the chemical potential generated by the proton (H+) gradient exists, a decrease in the electrochemical potential due to the lowered electrical potential (xcexa8m) may cause inhibition of the activities of ATP synthase, which finally results in cessation of the mitochondrial ATP synthesis.
It has been suggested that mitochondrial membranes may be depolarized by various exogenous and endogenous factors, and the depolarization may possibly be one cause of mitochondrial functional abnormality. Furthermore, mitochondrial functional abnormality is observed in various diseases, and the abnormality of mitochondrial function is considered as a major cause of some diseases. For example, the abnormality of mitochondrial function is generally recognized in ischemic diseases such as ischemic brain diseases and ischemic heart diseases, Parkinson""s disease, Alzheimer""s disease, amyotrophic lateral sclerosis (ALS), degenerative diseases due to mitochondrial abnormality such as mitochondrial encephalomyopathy, various toxic diseases such as carbon monoxide poisoning. A substance, which stabilizes mitochondrial membranes by protecting mitochondrial membranes from actions of various exogenous and endogenous factors and maintaining the physiological membrane potential, may be expected to be extremely useful for therapeutic and preventive and prophylactic treatment of these diseases.
An object of the present invention is to provide a substance which has an action of stabilizing mitochondrial membranes by protecting the mitochondrial membranes from actions of various exogenous and endogenous factors, and suppressing or eliminating the depolarization of mitochondrial membranes. Another object of the present invention is to provide a substance having actions of stabilizing mitochondrial membranes, and preventing the abnormality of mitochondrial function with depolarization of mitochondrial membranes. A further object of the present invention is to provide a medicament for prophylactic and/or preventive and/or therapeutic treatment of diseases caused by mitochondrial functional abnormality, or diseases with mitochondrial functional abnormality, which comprises a substance having the aforementioned actions as an active ingredient.
The inventors of the present invention conducted various studies to achieve the foregoing objects, and as a result, they first discovered the existence of a substance which has an action of stabilizing mitochondrial membranes by suppressing or eliminating the depolarization of mitochondrial membranes. The inventors of the present invention conducted further studies and found that, by stabilizing mitochondrial membranes, mitochondrial membranes can be protected from depolarization due to various exogenous and endogenous factors, and/or the physiological polarization condition of mitochondrial membranes can be maintained or restored, thereby physiological energy generation of mitochondria can be maintained or restored. It was also found that a substance having these actions can suppress an action of an agonist, that unstabilizes mitochondrial membrane, by binding as an antagonist to a benzodiazepine receptor present in mitochondrial membranes. The present invention was achieved on the bases of these findings.
The present invention thus provides a medicament for prophylactic and/or preventive and/or therapeutic treatment of a disease caused by mitochondrial functional abnormality, or a disease with mitochondrial functional abnormality, which comprises a substance having stabilizing effect on a mitochondrial membrane as an active ingredient. According to preferred embodiments of the aforementioned medicament of the present invention, there are provided the aforementioned medicament for prophylactic and/or preventive and/or therapeutic treatment wherein the stabilizing effect on the mitochondrial membrane is an action of suppressing or eliminating the depolarization of a mitochondrial membrane; the aforementioned medicament for prophylactic and/or preventive and/or therapeutic treatment wherein the depolarization of the mitochondrial membrane is caused by an elevated intracellular calcium ion concentration; the aforementioned medicament for prophylactic and/or preventive and/or therapeutic treatment wherein the stabilizing effect on mitochondrial membrane is an action of maintaining or restoring ATP producing ability of mitochondria under a physiological state when intracellular calcium ion concentration is elevated; and the aforementioned medicament for prophylactic and/or preventive and/or therapeutic treatment wherein the disease is selected from the group consisting of an ischemic disease, a toxic disease, and a degenerative disease. There is further provided the aforementioned medicament for prophylactic and/or preventive and/or therapeutic treatment wherein the substance is an antagonist for a mitochondrial benzodiazepine receptor.
According to preferred embodiments of the aforementioned medicament of the present invention, there are further provided the aforementioned medicament for prophylactic and/or preventive and/or therapeutic treatment wherein the ischemic disease is an ischemic affection of cranial nerve system or cerebral blood vessel system, ischemic heart disease, renal failure, or hepatic failure; the aforementioned medicament for prophylactic and/or preventive and/or therapeutic treatment wherein the degenerative disease is abnormality of mitochondrial enzyme activity, mitochondrial gene mutation disease, Parkinson""s disease, Alzheimer""s disease, amyotrophic lateral sclerosis (ALS), mitochondrial encephalomyopathy, or Niemann-Pick""s disease; and the aforementioned medicament for prophylactic and/or preventive and/or therapeutic treatment wherein the toxic disease is a gas poisoning, an alcoholic poisoning, a drug poisoning, a pesticide poisoning, a heavy metal poisoning, or a poisoning caused by a toxin derived from a natural animal or a natural plant.
According to another aspect of the present invention, there is provided a method for prophylactic and/or preventive and/or therapeutic treatment of a disease caused by mitochondrial functional abnormality, or a disease with mitochondrial functional abnormality, which comprises administering to a mammal including human an effective amount of a substance having a stabilizing effect on the mitochondrial membrane.
According to further aspects of the present invention, there are provided a mitochondrial membrane stabilizing agent which comprises an antagonist for a mitochondrial benzodiazepine receptor as an active ingredient; and a medicament for prophylactic and/or preventive and/or therapeutic treatment of a disease caused by mitochondrial functional abnormality, or a disease with mitochondrial functional abnormality, which comprises an antagonist for a mitochondrial benzodiazepine receptor as an active ingredient.